Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling

Björn C Knollmann; Paulus Kirchhof; Syevda G Sirenko; Hubertus Degen; Anne E Greene; Tilmann Schober; Jessica C Mackow; Larissa Fabritz; James D Potter; Martin Morad

doi:10.1161/01.RES.0000059562.91384.1A

Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling

Björn C Knollmann, Paulus Kirchhof, Syevda G Sirenko, Hubertus Degen, Anne E Greene, Tilmann Schober, Jessica C Mackow, Larissa Fabritz, James D Potter, Martin Morad

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

114 Citations (Scopus)

Abstract

The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca2+ transients and suppression of IK1.

Original language	English
Pages (from-to)	428-36
Number of pages	9
Journal	Circulation Research
Volume	92
Issue number	4
DOIs	https://doi.org/10.1161/01.RES.0000059562.91384.1A
Publication status	Published - 7 Mar 2003

Keywords

Action Potentials
Anesthesia
Animals
Blood Pressure
Calcium
Cardiomyopathy, Hypertrophic, Familial
Cardiotonic Agents
Electrocardiography
Genotype
Heart Ventricles
Humans
In Vitro Techniques
Isoproterenol
Mice
Mice, Transgenic
Mutation
Myocytes, Cardiac
Stress, Psychological
Tachycardia, Ventricular
Troponin T

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10.1161/01.RES.0000059562.91384.1A

Cite this

Knollmann, B. C., Kirchhof, P., Sirenko, S. G., Degen, H., Greene, A. E., Schober, T., Mackow, J. C., Fabritz, L., Potter, J. D., & Morad, M. (2003). Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling. Circulation Research, 92(4), 428-36. https://doi.org/10.1161/01.RES.0000059562.91384.1A

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title = "Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling",

abstract = "The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca2+ transients and suppression of IK1.",

keywords = "Action Potentials, Anesthesia, Animals, Blood Pressure, Calcium, Cardiomyopathy, Hypertrophic, Familial, Cardiotonic Agents, Electrocardiography, Genotype, Heart Ventricles, Humans, In Vitro Techniques, Isoproterenol, Mice, Mice, Transgenic, Mutation, Myocytes, Cardiac, Stress, Psychological, Tachycardia, Ventricular, Troponin T",

author = "Knollmann, {Bj{\"o}rn C} and Paulus Kirchhof and Sirenko, {Syevda G} and Hubertus Degen and Greene, {Anne E} and Tilmann Schober and Mackow, {Jessica C} and Larissa Fabritz and Potter, {James D} and Martin Morad",

year = "2003",

month = mar,

day = "7",

doi = "10.1161/01.RES.0000059562.91384.1A",

language = "English",

volume = "92",

pages = "428--36",

journal = "Circulation Research",

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Knollmann, BC, Kirchhof, P, Sirenko, SG, Degen, H, Greene, AE, Schober, T, Mackow, JC, Fabritz, L, Potter, JD & Morad, M 2003, 'Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling', Circulation Research, vol. 92, no. 4, pp. 428-36. https://doi.org/10.1161/01.RES.0000059562.91384.1A

TY - JOUR

T1 - Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling

AU - Knollmann, Björn C

AU - Kirchhof, Paulus

AU - Sirenko, Syevda G

AU - Degen, Hubertus

AU - Greene, Anne E

AU - Schober, Tilmann

AU - Mackow, Jessica C

AU - Fabritz, Larissa

AU - Potter, James D

AU - Morad, Martin

PY - 2003/3/7

Y1 - 2003/3/7

N2 - The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca2+ transients and suppression of IK1.

AB - The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy or fibrosis. Enhanced cardiac function has been associated with myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the present study, we compare cellular Ca2+ transients and electrophysiological parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated perfused hearts, and whole animals. Ventricular action potentials (APs) measured in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70% repolarization. No significant differences were found either in L-type Ca2+ or transient outward K+ currents, but inward rectifier K+ current (IK1) was significantly decreased. More critically, Ca2+ transients of field-stimulated ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+ exchanger was blocked by Li+. At higher pacing rates or in presence of isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared with control myocytes. Ventricular ectopy could be induced by isoproterenol-challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT) during mental stress (warm air jets). We conclude that the TnT-I79N mutation causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising possibly from the combination of AP remodeling related to altered Ca2+ transients and suppression of IK1.

KW - Action Potentials

KW - Anesthesia

KW - Animals

KW - Blood Pressure

KW - Calcium

KW - Cardiomyopathy, Hypertrophic, Familial

KW - Cardiotonic Agents

KW - Electrocardiography

KW - Genotype

KW - Heart Ventricles

KW - Humans

KW - In Vitro Techniques

KW - Isoproterenol

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Myocytes, Cardiac

KW - Stress, Psychological

KW - Tachycardia, Ventricular

KW - Troponin T

U2 - 10.1161/01.RES.0000059562.91384.1A

DO - 10.1161/01.RES.0000059562.91384.1A

M3 - Article

C2 - 12600890

SN - 0009-7330

VL - 92

SP - 428

EP - 436

JO - Circulation Research

JF - Circulation Research

IS - 4

ER -

Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling

Abstract

Keywords

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